Certain dihydrothiazines have been found to be active as anthelmintics and as insecticides. These dihydrothiazines are described by the formula: ##STR1## wherein R is a thienyl or furyl moiety, or one of these substituted by alkyl, and R.sup.1 contains from one to ten carbon atoms, and is an alkyl, alkenyl or alkynyl, cycloalkyl or cycloalkylalkyl, moiety, or one of these substituted by one or more of alkoxy and halogen, or is phenyl or benzyl, or one of these substituted by one or more of alkyl, alkoxy, halogen, haloalkyl, amino, alkylamino, dialkylamino, and nitro. Suitably, the defined aliphatic moieties are of either straight-chain or branched-chain configuration.
The compounds of Formula I usually exist as equilibrium mixtures with their tautomers of the formula: ##STR2## Usually, one or other of the tautomeric forms will predominate, possibly to the virtual exclusion of the other form, depending upon the nature of the R and R.sup.1 groups and the environment of the compounds (e.g., whether the compound is isolated in pure form, or as an acid-addition salt, or is in solution). The present invention extends to the individual tautomeric forms and to mixtures thereof. For brevity, the compounds of the invention are defined in terms of Formula I, the definition being intended to include the tautomeric form defined in Formula II.
Compounds of Formula I form acid-addition salts. The invention includes the pharmacologically acceptable acid-addition salts, such as those of hydrohalic acids, particularly hydrochloric and hydrobromic acids, and acetic, succinic, maleic, fumaric, propionic, citric, lactic, pamoic, tartaric, sulfuric and phosphoric acids.
Preferably, R.sup.1 represents alkyl of from one to six carbon atoms, cycloalkyl of from three to six carbon atoms or cycloalkylalkyl of from four to seven carbon atoms and R is 2-furyl, 2-thienyl or either substituted by one or more alkyl moieties of from one to four carbon atoms, particularly methyl.
The most active compounds appear to be those wherein R.sup.1 is alkyl of from one to four carbon atoms, or cyclopropylmethyl and R is 2-thienyl or 3-methyl-2-thienyl.
The compounds of Formula I can be prepared by treating a compound of the formula ##STR3## with 3-aminopropanethiol to give a compound of Formula I, optionally followed by exchanging the moiety R.sup.1 for another moiety R.sup.1.
The treatment of the compound of Formula III with 3-aminopropanethiol is advantageously carried out at elevated temperature in an inert solvent under an inert gas, such as nitrogen. For example, the reaction may be carried out in methylene chloride, at reflux temperature. If the 3-aminopropanethiol is initially in the form of an acid-addition salt, such as the hydrochloride, the reaction is desirably carried out in the presence of an organic base such as triethylamine.
The optional ester exchange reaction whereby one R.sup.1 moiety is substituted for a different R.sup.1 moiety may in general be effected by dissolving potassium metal in the appropriate hydroxy compound R.sup.1 --OH, advantageously in the presence of an inert solvent such as toluene, and adding to the resulting mixture the compound of Formula I (e.g. wherein R.sup.1 is methyl) and an appropriate molecular sieve (e.g. size 4A when the R.sup.1 group to be removed is methyl). The resulting suspension is heated, conveniently at reflux temperature, and the molecular sieve is subsequently removed by filtration.
The intermediates of Formula III may be prepared by reduction of compounds of the formula ##STR4## The reduction is conveniently effected using sodium borohydride similarly to the method of Kompis and Schonholzer, Helv. Chim. Acta, 1977, 60, 618. However, in suitable cases, e.g. when R is thienyl or alkylthienyl, catalytic hydrogenation, using, for example, palladium on charcoal as catalyst, may be employed.
The compounds of Formula IV may be prepared by Knoevenagel condensation of the appropriate aromatic aldehyde of the formula EQU R--CHO (V)
with the appropriate cyanoacetic ester of the formula EQU NC--CH.sub.2 --COOR.sup.1 (VI)
under conditions similar to those described by Popp, J. Org. Chem., 1960, 25, 646.
Dihydrothiazine derivatives of Formula I have utility as anthelmintics and as insecticides. They have low mammalian toxicity.
Accordingly, the invention also provides an anthelmintic or insecticidal composition comprising, as active ingredient, a compound of Formula I in association with a non-toxic carrier therefor. The invention further provides anthelmintic and insecticidal compositions which comprise a compound of Formula I in association with a non-toxic carrier therefor. Also provided in accordance with the invention is the use of a compound of Formula I as an anthelmintic or as an insecticide.
Further in accordance with the invention there is provided a method of combating parasitic worms which comprises subjecting the parasitic worms to exposure to an anthelmintically-effective dose of a compound of Formula I. The method has particular applicability when the parasitic worms are present in the alimentary tract of an animal and the Formula I compound is orally administered to the animal, and is particularly effective in combating parasitic worms in ruminants, e.g., sheep, pigs, cattle and goats.
Oral administration of the compound of Formula I may be by any convenient means, e.g. as a drench, by intubation, in the animal's food and water, in a food supplement or in specific formulations such as solutions, suspensions, dispersions, emulsions, tablets, boluses, powders, granules, capsules, syrups and elixirs. Suitable non-toxic carriers are the conventional, inert, pharmaceutically-acceptable carriers such as water, edible oils, gelatin, lactose, starch, magnesium stearate, talc or vegetable gum.
The dosage of the Formula I compound needed to combat parasitic worms will depend on the particular compound used and the animal being treated. However, in general, the compound will be administered in a dosage of from about 5 to about 200 milligrams per kilogram of the animal's body weight, typically from 10 to 30 milligrams per kilogram for sheep, pigs, goats and cattle. The compound can be administered in a single dose or in a series of doses in a day, or series of days. For any particular animal, a specified dosage regimen should be adjusted according to the individual need, the particular compound used and the professional judgment of the person administering or supervising administration of the compound.
The invention additionally provides a method of combating pests, such as insect pests, at a locus which comprises applying to that locus a pesticidally-effective amount of a compound of Formula I.
A carrier in a pesticidal composition of the invention may be a solid or a liquid, including a material which is normally gaseous but which has been compressed to form a liquid, inorganic or organic, and of synthetic or natural origin. The active ingredient is suitably formulated with at least one carrier to facilitate its application to the locus, for example, plants, seeds or soil, to be treated, or to facilitate storage, transport or handling.
Preferably, a pesticidal composition of the invention contains at least two carriers, at least one of which is a surface-active agent. The surface-active agent may be an emulsifier, a dispersing agent or a wetting agent; it may be non-ionic or ionic. Pesticidal compositions are generally formulated and transported in a concentrated form which is subsequently diluted by the farmer or other user before application. A surface-active agent facilitates this process of dilution.
Any of the carriers commonly used in the formulation of pesticides may be used in pesticidal compositions of the invention, and suitable examples of these are to be found, for example, in British Pat. No. 1,232,930.
Pesticidal compositions of the invention may, for example, be formulated as a wettable powder, microcapsules, a dust, granules, a solution, an emulsifiable concentrate, an emulsion, a suspension concentrate or an aerosol. The pesticidal composition may have controlled release properties, or may be suitable for use as a bait.
Wettable powders usually contain 25, 50 or 75%w of active ingredient and may contain, in addition to inert solid material, 3-10%w of a dispersing agent and, where necessary, 0-10%w of a stabilizer, a penetrant and/or a sticker. A dust is usually formulated as a dust concentrate having a composition similar to that of a wettable powder but without a dispersant, and is diluted in the field with further solid carrier to give a composition usually containing 0.5-10%w of active ingredient.
Granules usually have a size in the range of from 10 to 100 BS mesh (1.676-0.152 mm) and may be manufactured by agglomeration or impregnation techniques. Generally, granules will contain 0.5-25%w active ingredient and 0-10%w of additives, for example, a stabilizer, slow release modifier and/or a binding agent.
Emulsifiable concentrates usually contain, in addition to a solvent, and, when necessary, co-solvent, 10-50% w/v active ingredient, 2-20% w/v emulsifier and 0-20% w/v of other additives, for example, a stabilizer, a penetrant and/or a corrosion inhibitor. A suspension concentrate is a stable, non-sedimenting, flowable product and usually contains 10-75%w active ingredient, 0.5-15%w of dispersing agent, 0.1-10%w of suspending agent, for example, protective colloid and/or a thixotropic agent, and 0-10%w of other additives including, for example, a defoamer, a corrosion inhibitor, a stabilizer, a penetrant and/or a sticker, and as dispersant, water or an organic liquid in which the active ingredient is substantially insoluble; certain organic additives and/or inorganic salts may be dissolved in the dispersant to assist in preventing sedimentation or as anti-freeze for water.
The aqueous dispersions and emulsions formed by diluting a wettable powder or an emulsifiable concentrate of the invention with water, also lie within the scope of the present invention. Such dispersions and emulsions may be of the water-in-oil or of the oil-in-water type, and may have a thick 37 mayonnaise"-like consistency.
A pesticidal composition of the invention may also contain other ingredients, for example, one or more other compounds possessing pesticidal, herbicidal or fungicidal properties, or attractants, for example, pheromones or food ingredients, for use in baits and trap formulations.